A T-cell independent universal cellular therapy strategy through antigen depletion

Li, Dan; Wang, Wenbing; Xie, Shufeng; Ge, Maolin; Wang, Ruiheng; Xu, Qiongyu; Sun, Yan; Zhu, Jiang; Liu, Han

doi:10.7150/thno.66832

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Theranostics 2022; 12(3):1148-1160. doi:10.7150/thno.66832 This issue Cite

Research Paper

A T-cell independent universal cellular therapy strategy through antigen depletion

Dan Li^✉*, Wenbing Wang^*, Shufeng Xie^*, Maolin Ge^*, Ruiheng Wang^*, Qiongyu Xu, Yan Sun, Jiang Zhu, Han Liu^✉

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
* These authors contributed equally to this study.

Citation:

Li D, Wang W, Xie S, Ge M, Wang R, Xu Q, Sun Y, Zhu J, Liu H. A T-cell independent universal cellular therapy strategy through antigen depletion. Theranostics 2022; 12(3):1148-1160. doi:10.7150/thno.66832. https://www.thno.org/v12p1148.htm

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Abstract

Rationale: T cell therapeutic strategy using CD19-targeting chimeric antigen receptor (CAR) is a revolutionary, novel, and successful treatment for B-cell malignancies. However, the dependency on T-cell mediated cytotoxicity restricts CAR-T therapy as a patient-specific individualized therapy with severe side effects, such as cytokine release syndrome (CRS). Whether a non-T-cell based universal cellular therapy can substitute CAR-T therapy is largely unknown.

Methods: Various artificial antigen-recognizing cells were prepared to determine whether non-T-cell-derived CD19-scFv bearing effector cells could cause target cell death. A universal strategy for CRS-free cellular therapeutics was proposed, utilizing artificial antigen-recognizing cells (AARC), which can be manufactured universally and routinely as “off-the-shelf” mesenchymal stromal cells (MSCs) or other types of non-autologous cells expressing anergic CARs.

Results: We demonstrated that T-lymphocytic and non-lymphocytic cells could cause CD19 internalization and subsequent depletion when armed with a CD19-recognizing moiety. This CD19 antigen depletion could efficiently induce T-cell independent apoptosis in target cancer cells whose survival depends on CD19 expression, suggesting that CD19 antigen depletion constitutes a crucial tumor destroying mechanism for CD19-CAR-T, especially for its long-term efficacy.

Conclusion: Our results uncovered an unrecognized CAR-T cytotoxicity and antigen loss mechanism and provided new insights into a shift from unique patient-specific autologous therapeutics to universal and standardized allogeneic treatment.

Keywords: cellular therapy, CD19, CAR-T, cytokine release syndrome, artificial antigen-recognizing cell

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APA

Li, D., Wang, W., Xie, S., Ge, M., Wang, R., Xu, Q., Sun, Y., Zhu, J., Liu, H. (2022). A T-cell independent universal cellular therapy strategy through antigen depletion. Theranostics, 12(3), 1148-1160. https://doi.org/10.7150/thno.66832.

ACS

Li, D.; Wang, W.; Xie, S.; Ge, M.; Wang, R.; Xu, Q.; Sun, Y.; Zhu, J.; Liu, H. A T-cell independent universal cellular therapy strategy through antigen depletion. Theranostics 2022, 12 (3), 1148-1160. DOI: 10.7150/thno.66832.

NLM

CSE

Li D, Wang W, Xie S, Ge M, Wang R, Xu Q, Sun Y, Zhu J, Liu H. 2022. A T-cell independent universal cellular therapy strategy through antigen depletion. Theranostics. 12(3):1148-1160.

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